Process for the synthesis of 2,4-dinitro-6-t-butyl-3-methylanisole, referred to as musk ambrette

ABSTRACT

The invention relates to a process for the synthesis of 2,4-dinitro-6-t-butyl-3-methylanisole or musk ambrette. 
     The process according to the invention is characterized in that 6-t-butyl-3-methylanisole is reacted with a nitrating mixture consisting of 30 to 50% of acetic acid, 20 to 30% of acetic anhydride and 25 to 45% by weight of nitric acid, at between 7° and 15° C. The product is recovered in the pure state with a good yield by adding small amounts of water to the crude reaction mixture. 
     Application: Synthesis of a scented product.

This is a division of application Ser. No. 970,139 filed Dec. 18, 1978and now U.S. Pat. No. 4,236,029.

The present invention relates to a process for the preparation of2,4-dinitro-6-tert.-butyl-3-methylanisole.

2,4-Dinitro-6-t-butyl-3-methylanisole is better known by the name MuskAmbrette and is widely used as a scent. By virtue of the fact that, inthis latter respect, it is of greater value than homologous compounds,this product is in particularly high demand.

Several processes for the manufacture of Musk Ambrette were proposed arelatively long time ago. TCHICHIBABINE, in the Bulletin de la SocieteChimique de France of 1939, volume 4, page 439, recommended startingfrom 3-methyl-6-t-butylphenol and successively nitrating it (usingnitric acid) and methylating the phenol group (using dimethyl sulphate)in accordance with equations (I) and (II) below: ##STR1## However, thisis not an industrial process because the reactions take place withdifficulty and give rise to a mixture of isomers or of homologues.

CARPENTER, EASTER and WOOD, in volume 16, No. 4, pages 586-617 of theJournal of Organic Chemistry of 1951, proposed to nitrate3-methyl-6-t-butylanisole, at between -10° and +20° C., using a mixtureof 98% strength nitric acid (5 mols) and acetic anhydride (3.5 mols).However, although this process indeed makes it possible to obtain MuskAmbrette with fairly good yields, it requires, on the other hand, theuse of a nitrating mixture which is very rich in nitric acid (about 50%)in order for total nitration to be achieved. In fact, this processrequires the use of temperatures well below normal temperature,generally substantially below 0° C. and preferably in the region of -15°C.

However, despite these rather restrictive conditions, it is not possibleto obtain a product of satisfactory purity directly in the crudereaction mixture, as proved by the works of S. ABE which appeared involume 21, No. 12, pages 936-940 of Yuki Gosci Kayaku Kyokai Shi of 1963(Chemical Abstracts 60:4038a). In fact, it is not possible to avoid theproduction of quinone derivatives and especially the removal of thetert.-butyl group from the molecule.

Finally, it has been proposed to avoid the temperature constraints byusing a special apparatus for continuous nitration. This apparatus,described by Gel'Perin et al. in Zhur. Vsesojuz Khim. Obshchestra im.D.I. Mendeleeva (1960), 5, pages 438-442, requires a large investmentwhich increases the production costs to a prohibitive degree.Furthermore, this process does not make it possible to resolve thedifficulty of the separation and purification of the product formed.

A common feature of the former processes is that the reaction mixture isfinally poured onto ice or cold water in order to separate out theorganic phase and wash the nitrated product. The latter is thengenerally taken up in an organic solvent and subsequently re-washeduntil neutral, after which the organic solvent is evaporated off and theMusk Ambrette is recrystallised. It is clear that these essentialoperations increase the cost price of the Musk Ambrette obtained by theformer processes.

The Applicant Company has now discovered a process for the manufactureof Musk Ambrette, which makes it possible to use a nitrating mixturecontaining relatively little nitric acid and an easily accessibletemperature. This process additionally makes it possible to recover MuskAmbrette of satisfactory purity particularly easily, the overall yieldof the process being at least equal to the yields of the olderprocesses.

The process according to the invention fundamentally consists intreating 3-methyl-6-t-butylanisole with a ternary nitrating mixturecomprising acetic anhydride, nitric acid and acetic acid, at atemperature between +5° and +30° C. and preferably between 7° and 15° C.

According to a preferred variant of the process according to theinvention, the nitrating mixture used initially comprises a total of 30to 50% by weight of acetic acid, 20 to 30% by weight of acetic anhydrideand 25 to 45% by weight of nitric acid.

The terms acetic acid and nitric acid are to be understood as meaningconcentrated acids of the usual technical purity, that is to say acidscontaining at least 97% by weight of CH₃ COOH and HNO₃ respectively. Ofcourse, it is also possible to prepare the mixture according to theinvention by using less acetic acid, more acetic anhydride and anaqueous solution of nitric acid of, for example, 70% strength. However,this is of less value.

The process according to the invention can be applied for nitratingratios of between 5 and 6, the nitrating ratio being the ratio of themass of nitrating mixture to the mass of substance to be nitrated. Thus,it is possible to use from 3.5 to 7.5 mols, and preferably from 4.5 to5.5 mols, of nitric acid per mol of t-butyl-methylanisole to benitrated.

In accordance with the process according to the invention, it has beenfound advantageous first to prepare a sediment comprising the nitratingmixture or only some of the constituents of this mixture, and then tointroduce the t-butyl-methylanisole, pure or in solution, and, ifnecessary, the remainder of the constituents of the nitrating mixture.For example, the butylmethylanisole can be in solution in aceticanhydride.

According to a particularly preferred variant, t-butyl-methylanisole isintroduced, at the same time as all or part of the nitric acid, onto asediment mixture consisting of acetic acid, acetic anhydride and, ifnecessary, the remainder of the nitric acid.

As the reaction is violently exothermic, the t-butyl-methylanisole mustbe introduced gradually, with the result that the reaction time largelydepends on the amounts of reactants employed. In general, however, thereaction conditions defined in the present process make it possible tocomplete the introduction, which is preferably slow at the start, withina period of between 20 minutes and 2 hours, the reactor being cooled ina simple manner using brine.

When the introduction is complete, the reaction is already veryadvanced, but the stage in which all the reactants are brought intocontact should be followed by a stage for completion of the reaction,which consists in leaving the reaction mixture for 20 to 90 minutes atambient temperature (about 25° C.), whilst stirring moderately (themedium is homogeneous).

The Musk Ambrette can be recovered either by precipitating the crudereaction mixture obtained after the completion stage onto a mixture ofwater and ice, in a manner which is in itself known, or by introducinginto the said mixture, preferably slowly and whilst stirring, one ormore amounts of water which are small compared with those employed inthe preceding method and less than 100% by weight of the amount ofnitrating mixture used. In the first case, it is necessary to take upthe product in an organic solvent such as benzene or, preferably,hexane. In the second case, it has been discovered that the MuskAmbrette precipitates with an astonishing yield and purity.

In particular, if a first amount of water is introduced which representsfrom about 5 to 40% by weight of the nitrating mixture involved in thereaction, a first precipitate of Musk Ambrette of excellent purity isobtained (sharp melting point between 83° and 85° C. and generally about84° C.) with a yield of 40 to 65%, relative to thet-butyl-methylanisole. By adding, in the same manner, one or moreadditional small amounts of water, each representing from 1 to 15% byweight of the initial nitrating mixture, further amounts of MuskAmbrette of deteriorating grade, which can nevertheless be suitable formost industrial applications, are precipitated and collected betweeneach addition.

According to another variant, an amount of water representing, byweight, from 25% to 100% of the weight of the nitrating mixture used isintroduced all at once into the crude reaction mixture. This then givesa precipitate of pure Musk Ambrette (melting point above 83° C.) with ayield of 55 to 70%.

In each case, it is possible to further improve the purity of therecovered products by means of a clearing operation using an ice-cooledalcohol, for example methanol or isopropanol. Furthermore, it has beenfound advantageous to cool the crude synthesis mixture slightly to atemperature which is preferably between 15° and 20° C., beforeintroducing the water and therefore carrying out the precipitation. Inorder to complete this precipitation, it is also advantageous to stirthe medium moderately for 15 to 45 minutes.

Finally, it can be considered that, when 100 to 200% by weight of water,relative to the nitrating mixture involved in the synthesis, has beenintroduced into the reaction medium, all the Musk Ambrette of marketablepurity, which is produced by the process according to the invention andseparated by fractional precipitation, has been recovered; the yield ofthe synthesis is 60 to 85%, depending on the desired degree of purity ofthe Musk Ambrette.

The process according to the invention uses much milder conditions thanthe processes of the prior art. It is completely surprising that abetter purity and yield are obtained under these conditions.

Furthermore, it must be appreciated that HNO₃ /acetic anhydride mixturesmust be handled with great precautions, because it has been shown thatsuch mixtures can explode. The invention therefore represents a distinctadvance both from the technical point of view (less harsh nitratingbath, improved yield, purity and recovery and lower reactiontemperature) and from the point of view of safety.

Further advantages of the invention will become apparent in thefollowing examples which must not be considered as limiting theinvention.

EXAMPLE 1

A kilogram of a sediment consisting of 40% of acetic acid, 28% of aceticanhydride and 32% of 98% strength nitric acid was prepared.

The temperature of the medium was kept at 25° C., using a brine bath,and 178 g of 6-t-butyl-3-methylanisole were run into this nitrating bathin the course of 1 hour, whilst stirring.

Once the introduction was complete, the reaction medium was kept at 25°C. for half an hour. The mixture obtained was then poured onto a mixtureof water and ice. The organic phase was taken up in 1,500 ml of hexaneand, after evaporating off the solvent, 262 g of a product having amelting point of 64° C. and containing 80% of Musk Ambrette werecollected. The yield of this product is therefore 76%.

EXAMPLE 2

178 g of 3-methyl-6-t-butylanisole and 330 g of 98% strength nitric acidwere run simultaneously, in the course of one hour, into 670 g of asediment consisting of 52% of acetic acid and 48% of acetic anhydride,keeping the temperature at 25° C. and whilst stirring the medium.

After having left the mixture to stand for 30 minutes at 25° C., it waspoured onto ice and 240 g of product, containing 88% of Musk Ambretteand having a melting point of 64° C., were collected by taking up themixture in 1,500 ml of hexane. The yield of pure Musk Ambrette from thereaction is 78%.

EXAMPLE 3

17.8 g of 3-methyl-6-t-butylanisole and 16 g of nitric acid (98%strength) were introduced, in the course of one hour, into 84 g of asediment consisting of 49% of acetic acid, 31% of acetic anhydride and20% of nitric acid, keeping the temperature of the medium at 10° C.

After having stirred the medium moderately for one hour at 25° C., 22 mlof water were introduced into the said medium and 11.5 g of MuskAmbrette, which had precipitated, were collected. This product had amelting point of 84° C. and represented 43% of the theoretical yield.

30 ml of water were then introduced into the medium and 7.8 g of Muskhaving a melting point of 74° C. were precipitated.

By adding 200 ml of water, a further 3.2 g of a product containing about50% of Musk were collected.

Determination of the crude reaction product showed that it contained 71%of Musk.

EXAMPLE 4

The conditions of Example 3 were repeated, using amounts which were tentimes greater.

Thus, 250 ml of water were introduced into the medium obtained. 140 g(52% of theory) of pure Musk Ambrette, having a melting point of 85° C.,were collected.

A second addition of 100 ml of water made it possible to collect 58 g ofMusk having a melting point of 73° C.

A third addition of 100 ml gave a further 12 g of product having amelting point of 72° C. and a last addition of 1,000 ml gave 24 g ofproduct containing only 30% of Musk.

The crude yield of Musk from the reaction is 72%.

EXAMPLE 5

The conditions of Example 4 were repeated, but 300 ml of water wereadded all at once.

166 g of pure Musk Ambrette, having a melting point of 84° C., werecollected with a yield of 62%, relative to the theoretical amount.

The medium was then immersed in one liter of water and 60 g of aprecipitate of impure product containing 30% of Musk were collected.

EXAMPLE 6

If 330 ml of water are run into the crude reaction mixture obtained inExample 5, 185 g of Musk Ambrette, containing more than 99% of Musk andmelting at 84° C., are collected. The yield of product of excellentpurity is therefore 69%.

EXAMPLE 7

If 280 ml of water are run into the crude reaction mixture obtained inExample 5, which has been cooled to about 18° C., 162 g of very puremusk, melting at 85° C., are collected after having stirred the mixturefor 30 minutes at 18° C. (yield 61%). If an additional 110 ml are runin, a further 65 g of 65% pure Musk, melting at 73° C., are collected.

If a further 110 ml are run in, 13 g of impure precipitate are recoveredand, if the medium thus obtained is immersed, a further 27 g of product,containing 30% of musk and 70% of 4,6-dinitro-3-methylanisole, arerecovered.

The overall yield of pure Musk Ambrette from the reaction is 81%, nearlythree quarters of which has therefore been collected in the pure state.

We claim:
 1. Process for the synthesis of2,4-dinitro-6-t-butyl-3-methylanisole which consists of reacting3-methyl-6-t-butylanisole with a ternary nitrating mixture whichcomprises acetic anhydride, acetic acid and nitric acid at between 5°and 30° C. wherein said nitrating mixture consists of a total of 30 to50% by weight of acetic acid, 20 to 30% by weight of acetic anhydrideand 25 to 45% by weight of nitric acid, and said2,4-dinitro-6-t-butyl-3-methylanisole is recovered as a precipitate byintroducing into the crude reaction mixture, preferably slowly and whilestirring, one or more small amounts of water which are less than 100% byweight of the amount of nitrating mixture used.
 2. Process according toclaim 1, wherein an amount of water representing, by weight, from 25 to100% of the weight of the nitrating mixture used is introduced all atonce into the crude reaction mixture.
 3. Process according to claim 1,wherein a first amount of water, representing from 5 to 40% by weight ofthe nitrating mixture used, is introduced and the precipitate of2,4-dinitro-6-t-butyl-3-methylanisole obtained is collected, and one ormore small amounts of water, each representing from 1 to 15% by weightof the nitrating mixture, are then introduced, additional amounts ofsaid product of deteriorating grade are collected between each addition.4. Process according to claim 1, wherein the temperature of the crudereaction mixture is brought to between 15° and 20° C. before the wateris introduced.